PCR Stands Firm Behind Paclitaxel-Coated Devices in PAD

Patrice Wendling

May 22, 2019

PARIS — The much-publicized Katsanos meta-analysis that effectively put paclitaxel-based balloons and stents on hold globally for peripheral artery disease (PAD) met with unvarnished opposition at one of the world's largest gatherings of cardiovascular interventionalists.

Before she could even review the evidence for the audience, the author of a formal PCR statement on the controversy was called to the stage at the European Association of Percutaneous Cardiovascular Intervention (EuroPCR) 2019 to discuss "our typhoon in a teapot."

"That's a very nice introduction and I think you described it very well," responded Alexandra Lansky, MD, Yale University School of Medicine, New Haven, Connecticut, who went on to dismantle the meta-analysis and question the biological plausibility of a link between paclitaxel-coated balloons and excess mortality.

As previously reported, the safety debate has been swirling since December when the Katsanos meta-analysis of 28 randomized controlled trials reported a 68% relative risk increase in all-cause death at 2 years that increased to 93% at 5 years with use of paclitaxel-coated devices vs noncoated devices in patients with PAD.

As a result, the European SWEDEPAD and BASIL-3 PAD trials suspended enrollment, the US Food and Drug Administration (FDA) announced its own investigation, and device makers began reporting their own findings.

"At least four new patient-level analyses and a large-scale claims data analysis have failed to replicate the results of the meta-analysis with DCB [drug-coated balloons]," Lansky observed. "And the coronary application has never been associated with a long-term safety signal. So, the position is that currently there is no strong evidence for a mortality signal."

The meta-analysis "has major inherent methodologic limitations that prevent reliable interpretation of the primary findings," she said. These include study-level rather than patient-level data; limited long-term data with more than 80% loss of patients at 4 to 5 years and more than 35% loss to follow up; unmeasured crossovers and reinterventions; unknown additional paclitaxel exposure; lack of adjudication of cause of death; errors in published death rates with subsequent corrections; and a lack of plausible explanation for a dose response.

Many of these issues were aired during a Vascular Leaders Forum specifically convened in March to tackle the controversy and where the FDA acknowledged it too had identified an excess of mortality.

After initially taking no stance, the FDA subsequently advised physicians in a warning letter that "alternative treatment options should generally be used for most patients" in light of its finding of about a 50% increase in mortality with paclitaxel-coated devices in three trials with 5-year follow-up data.

Last month, the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) issued similar advice, while the Society for Vascular Surgery told its members, "Given the conflicting conclusions about a paclitaxel dose effect, even proceeding but choosing a lower-dose device seems unsubstantiated."

The PCR statement, however, came to a different conclusion.

"Until more robust data to the contrary, there is currently no strong evidence to justify changing clinical practice and clinicians should continue to use best judgment," Lansky said during the hotline session.

PCR says the Katsanos meta-analysis results cannot be ignored because of the mortality implication and acknowledges the need for a more reliable industry-wide patient level and DCB-only pooled analysis, which is expected to be presented at an upcoming FDA meeting June 19 and 20.

Asked by theheart.org | Medscape Cardiology how PCR could come to such different advice than the FDA and others, Lansky said, "I don't think it's really opposite. It's saying we take this seriously; we need more evidence but the evidence isn't strong enough right now to convince us this truly is a problem and to change practice."

"Having said that, we'll leave it up to all the clinicians," she said. "But what we need to do is to push forward. We need the evidence. We need the clinical trials. Right now, with the warning coming from the FDA, everything's on standby and I don't think that's the right answer for this."

This is particularly true in light of the fact that such a small proportion of individuals with long-term follow-up in the Katsanos meta-analysis were DCB patients, Lansky observed.

"Is this a DCB issue? Is this a DES [drug-eluting stent] issue? We don't know, but the benefit, the efficacy of DCBs, is very strong," Lansky said. "It is a good therapy for a very difficult-to-treat population, so we just need more information."

To that end, the PCR statement "strongly encourages" resuming previously suspended prospective randomized DCB trials, including SWEDEPAD and BASIL 3, under careful adjudication and safety oversight, as these will provide the evidence necessary to address the safety of DCB.

Lansky noted that some PAD studies are still ongoing but acknowledged that enrollment in trials such as SWEDEPAD and BASIL-3 may be challenging given the mortality concerns.

Panelist Hany Eteiba, MD, Golden Jubilee National Hospital, Clydebank, Scotland, also suggested that the explanations for the mortality signal are biologically and clinically implausible and said the controversy is reminiscent of the 2006 firestorm that erupted over a registry-identified late mortality signal with drug-eluting stents.

"I'm delighted with the conclusion that you reached and it's a very fair conclusion," Eteiba said.

Lansky reports research grant support from AstraZeneca, Abiomed, Abbott Vascular, Bard, Boston Scientific, Biocardia, Biotronik, Cagent, Cardiatis, Conformal, Gore, Intact Vascular, KeyStone Heart, Venous, Lifetech, Limflow, Medinol, Micell, Microport, Myocardia, Reva, Shockwave Medical, Surmodics, TriReme, Venus, and Veryan Medical.

European Association of Percutaneous Cardiovascular Intervention (EuroPCR) 2019: PCR Statement on clinical outcomes after interventions with paclitaxel-drug coated balloons. Presented May 21, 2019.

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